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Lipoproteins/Apolipoproteins Background

To fulfill their roles in lipid and lipoprotein metabolism, the protein components of lipoproteins, the apolipoproteins, function in multiple ways as activators or inhibitors of enzymes or proteins such as LCAT, LPL and CETP, or as ligands for receptors and as recruiters for lipid. ApoB48 and apoB100 are major non-exchangeable apolipoproteins that remain associated with the lipoprotein particle. Other apolipoproteins, such as apoAs, apoCs, and apoE, are exchangeable apolipoproteins. They can be exchanged among different lipoproteins and the aqueous environment in plasma.



ApoA-l, the major protein component of HDL, is both necessary and sufficient for the formation of HDL. ApoA-l plays an important role in the RCT pathway by: a) interacting with the cell membrane transporter ABC-A1 and promoting cell cholesterol efflux, b) activating LCAT, the enzyme involved in cholesterol esterification, and c) carrying the excess esterified cholesterol back to the liver for excretion through the interaction with cell surface receptor SR-BI which mediates the selective uptake of HDL cholesterol ester. The plasma levels of apoA-l and mature HDL correlate inversely with the probability of developing atherosclerosis. In order to understand the mechanism of the function of apoA-l and find out possible ways for therapy, numerous research activities have been focused on this protein.



ApoE, a major apoprotein of chylomicrons and VLDL, is a ligand for the LDL-receptor on liver cells and peripheral cells and is important for the metabolism of these triglyceride-rich lipoproteins.

ApoE is 299 amino acids long and synthesized principally in the liver. In the three isoforms observed, apoE3 is the most common isoform, apoE2 contains a single mutation R158C and apoE4 contains another single mutation C112R. Residues 139-146 of apoE3 are the LDL receptor binding region. ApoE4 is involved in neurodegenerative disorders such as Alzheimer's disease. Compared to apoE3 and apoE4, apoE2 binds to LDL receptor much more weakly and is associated with type III hyperlipidema as a result.

Like apoA-l, apoE can switch between lipid-free and lipid bound states. The primary sequence also contains 22 amino acid repeats that may form α helical lipid-binding domains. The N-terminal domain in the lipid-free state is an elongated four-helix bundle as determined by X-ray crystallography and has a low affinity for lipid. The C-terminal domain of apoE contains high a-helical content and the major lipid-binding elements (residues 244-272). Its detailed structure is unknown.



ApoA-IV, the largest exchangable protein component of chylomicrons, VLDL and HDL, plays a role in chylomicron assembly, RCT and appetite regulation. ApoA-IV is 376 amino acids long and is encoded by genes located at the same region as apoA-l and apoC-lll on human chromosome 11. It is principally synthesized by enterocytes of the small intestine during chylomicron assembly, but may also have a role in VLDL secretion. Upon chylomicron reaction with LPL, apoA-IV rapidly dissociates from the surface and becomes lipid-free protein or associated with HDL.

Like other exchangeable apolipoproteins, especially apoA-l and apoE, apoA-IV contains multiple 22-residue amphipathic a-helical repeats that are mostly punctuated by proline residues. It can also switch between lipid-free and lipid-bound state, which may perform distinct functions. But unlike apoA-l and apoE that are characterized by a well-organized N-terminal helix bundle domain in the lipid-free state and a high lipid-affinity C-terminal domain, apoA-IV constitutes a single large domain. Mutation studies show that the Cterminal 44 residues have an inhibitory effect on lipid-binding ability. The three dimensional structure of apoA-IV is still lacking.


A common structural motif of exchangeable apolipoproteins

The amphipathic α-helices that exist in the major exchangeable apolipoproteins, apoA-l, apoA-IV and apoE, were first proposed by Segrest et al. as a unique structural and functional motif of apolipoproteins involved in lipid interaction. Amphipathic helix motifs were also found in other lipid-associated proteins and were later classified into seven classes (A, H, L, G, K, C, and M) based on the physico-chemical and structural properties. Most amphipathic helices in exchangeable apolipoproteins were predicted to belong to class A, which has negatively charged residues at the center of the polar side, hydrophobic/non-polar residues at the other side and positively charged residues at the polar-nonpolar interface. The apolar surface area provides the lipid binding ability. The 11/22-mer repeats in the primary sequences of exchangeable apolipoproteins are predicted to be the residues forming the amphipathic a-helices that are believed to play a key role in apolipoprotein lipid binding.

Genomic studies of apolipoproteins show that the genes encoding apoA-l, A-ll, Cs and E form an apolipoprotein multigene superfamily. ApoA-IV is located at the same tandem region as apoA-l and CI 11 on the chromosome. Their genomic structures are very similar in that the last exon (exon3 for apoA-IV and exon4 for others) contains a variable number of internal repeats of 11 codons. The genes of all these exchangeable apolipoproteins are possibly derived from a common ancestor gene sequence as a result of multiple partial and complete gene duplications and deletions.

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